Alarming increase in ketoacidosis in children and adolescents with newly diagnosed type 1 diabetes during the first wave of the COVID-19 pandemic in Israel.

OBJECTIVE: To evaluate the incidence and severity of ketoacidosis (DKA) at type 1 diabetes diagnosis during the first wave of the coronavirus disease 2019 (COVID-19) pandemic in Israel. RESEARCH DESIGN AND METHODS: A population-based study the product of a national collaboration of Israeli pediatric diabetes centers investigated the presentation of childhood-onset type 1 diabetes. The frequencies of DKA and severe DKA observed during the COVID-19 period from March 15, 2020 (commencement of the first nationwide lockdown) until June 30, 2020 were compared with the same periods in 2019, 2018, and 2017 using multivariable logistic regression, adjusting for age, sex, and socioeconomic position. RESULTS: During the COVID-19 period, DKA incidence was 58.2%, significantly higher than in 2019 (adjusted OR [aOR] 2.18 [95% CI, 1.31-3.60], P = 0.003); 2018 (aOR 2.05 [95% CI, 1.26-3.34], P = 0.004); and 2017 (aOR, 1.79 [95% CI, 1.09-2.93], P = 0.022). The incidence of severe DKA was 19.9%, significantly higher than in 2018 (aOR, 2.49 [95% CI, 1.20-5.19], P = 0.015) and 2017 (aOR, 2.73 [95% CI, 1.28-5.82], P = 0.009). In 2020, admissions and duration of stay in the intensive care unit were higher than in previous years (P = 0.001). During the COVID-19 pandemic, children aged 6-11 years had higher incidences of DKA (61.3% vs. 34.0%, 40.6%, and 45.1%, respectively, P = 0.012), and severe DKA (29.3% vs. 15.1%, 10.9%, and 5.9%, respectively, P = 0.002). CONCLUSIONS: The dramatic increase in DKA at presentation of childhood-onset type 1 diabetes during the COVID-19 pandemic mandates targeted measures to raise public and physician awareness.

Long duration of hyperglycemia in the first 96 hours of life is associated with severe intraventricular hemorrhage in preterm infants.

OBJECTIVE: To assess the association between severe intraventricular hemorrhage (IVH) and blood glucose variables during the first 96 hours of life in preterm infants. STUDY DESIGN: Preterm infants with IVH grade 3-4 (n = 70) were compared with matched infants of similar gestational age and birth weight, but with no IVH (n = 108). Studied variables included the frequency and duration of hyper/hypoglycemic (>6.9/<3.3 mmol/L, respectively) events, the extreme slope of an event evolution, the maximal glucose value observed, and the "hyper/hypoglycemic index" representing a weighted average of the hyper/hypoglycemic amplitude. RESULTS: The IVH group had significantly more hyperglycemic events (2.9 ± 1.7 vs 2.4 ± 1.8 events, P < .05) with longer duration (22.2 ± 14.2 vs 14.1 ± 12.5 hours, P < .001) and a higher hyperglycemic index (1.0 ± 0.9 vs 1.4 ± 1.0, P = .003) compared with the non-IVH controls. Respiratory distress syndrome, hypotension, and thrombocytopenia increased the adjusted OR for IVH. Hypoglycemia was not independently associated with IVH. Conversely, the increase in hyperglycemic duration was most prominently increasing the aOR for severe IVH (OR = 10.33, 95% CI = 10.0-10.6, P = .033). CONCLUSION: Longer duration of hyperglycemia in the first 96 hours of life was most strongly associated with severe IVH in preterm infants. Consequently, interventional studies to determine the selective effect of continuous control of long-lasting hyperglycemia by appropriate and timed insulin treatment on the incidence of severe IVH are warranted.

Glucose levels are not the same for everyone: a real-world big data study evaluating fasting serum glucose levels by sex and age among children.

OBJECTIVES: Understanding the normal range of laboratory values as pertained to different age groups and males or females is paramount in health care delivery. We aimed to assess the distribution of morning fasting serum glucose levels by age and sex in the general population of children using a large-scale population-based cohort. METHODS: A retrospective study with real-world de-identified data from a large, state mandated health fund in Israel among children aged 2-18 years old between 2006 and 2019. Age, sex, and BMI differences in mean glucose levels were evaluated. RESULTS: Study included 130,170 venous blood samples from 117,411 children, 53.3 % were female. After adjusting for age boys had higher fasting serum glucose levels than girls, with a mean of 89.21 ± 8.66 mg/dL vs. 87.59 ± 8.35 (p<0.001) [4.95 ± 0.48 mmol/L vs. 4.86 ± 0.46]. Compared to the 15 to 18 year-olds (88.49 ± 7.63 mg/dL) [4.92 ± 0.42 mmol/L], 2 to 5 year-olds had lower glucose levels (84.19 ± 10.65, [4.68 ± 0.59] (p<0.001)), 11 to 14 year-olds had higher glucose (90.40 ± 7.42 [5.02 ± 0.41], (p<0.001)) and 6 to 10 year-olds showed no difference (88.45 ± 8.25) [4.91 ± 0.46]. 33.0 % (n=42,991) had a BMI percentile record the same year as their glucose test result. There was a weak yet significant positive association between blood glucose levels and BMI. CONCLUSIONS: Our large cohort indicates that boys have slightly higher fasting serum glucose levels than girls, as do adolescents compared to younger children. This finding is important for the delivery of adequate health care, screening for illness and avoiding unnecessary investigations and tests.

Multisystem Inflammatory Syndrome in Children Associated With Severe Acute Respiratory Syndrome Coronavirus-2 in an 8-Week-Old Infant.

We describe an 8-week-old infant with severe gastrointestinal symptoms, significant hypoalbuminemia, and mild carditis following asymptomatic infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The infant's symptoms, including their temporal appearance, were consistent with multisystem inflammatory syndrome in children (MIS-C). A unique finding on colonic histology which may shed light on the pathogenesis of MIS-C was identified. The patient improved significantly following several anti-inflammatory treatments. The lag between the presentation of MIS-C and initial SARS-CoV-2 exposure, which may often be asymptomatic, together with the young age of our patient, makes this a challenging diagnosis. Clinicians should be aware of this entity, even in the neonatal and infantile age groups, to facilitate timely identification and treatment.

The inter - Test variability of growth hormone stimulation tests and factors affecting this variability.

OBJECTIVE: To evaluate the variability of growth hormone stimulation tests results and factors affecting it in short children suspected of having growth hormone deficiency. DESIGN: The cohort included patients with short stature suspected of having growth hormone deficiency, and who underwent a second stimulation test, after the first stimulation test was positive. Testing was done at a single center from May 2014 to October 2017. Patients' weight, height, age, sex, stimulating agents and test results were recorded. RESULTS: The study population comprised 200 patients, 108 males and 92 females, average age 9.2 years (2.2-16.6 years). The average peak growth hormone was 5.2 µg/L and 7.8 µg/L in the first and second tests respectively and the concordance rate was 56.5%. The probability of a second positive test was increased if the peak growth hormone level in the first test was below 5 µg/L. In the second test, Clonidine and Glucagon led to higher peak growth levels than Arginine with averages of 9.02, 9.97 and 6.88 µg/L respectively. Younger children and children with higher BMI SDS only had lower peaks of growth hormone in the second test. The effect of height SDS on peak growth hormone levels was equivocal. CONCLUSION: The reproducibility rate of GH simulation tests in our study was low. A few factors may affect the peak levels of growth hormone in the second test, the most prominent being the peak of growth hormone in the first test.

NKX2-2 Mutation Causes Congenital Diabetes and Infantile Obesity With Paradoxical Glucose-Induced Ghrelin Secretion.

CONTEXT: NKX2-2 is a crucial transcription factor that enables specific ß-cell gene expression. Nkx2-2(-/-) mice manifest with severe neonatal diabetes and changes in ß-cell progenitor fate into ghrelin-producing cells. In humans, recessive NKX2-2 gene mutations have been recently reported as a novel etiology for neonatal diabetes, with only 3 cases known worldwide. This study describes the genetic analysis, distinctive clinical features, the therapeutic challenges, and the unique pathophysiology causing neonatal diabetes in human NKX2-2 dysfunction. CASE DESCRIPTION: An infant with very low birth weight (VLBW) and severe neonatal diabetes (NDM) presented with severe obesity and developmental delay already at age 1 year. The challenge of achieving glycemic control in a VLBW infant was unexpectedly met by a regimen of 3 daily doses of long-acting insulin analogues. Sanger sequencing of known NDM genes (such as ABCC8 and EIF2AK3) was followed by whole-exome sequencing that revealed homozygosity of a pathogenic frameshift variant, c.356delG, p.P119fs64*, in the islet cells transcription factor, NKX2-2. To elucidate the cause for the severe obesity, an oral glucose tolerance test was conducted at age 3.5 years and revealed undetectable C-peptide levels with a paradoxically unexpected 30% increase in ghrelin levels. CONCLUSION: Recessive NKX2-2 loss of function causes severe NDM associated with VLBW, childhood obesity, and developmental delay. The severe obesity phenotype is associated with postprandial paradoxical ghrelin secretion, which may be related to human ß-cell fate change to ghrelin-secreting cells, recapitulating the finding in Nkx2-2(-/-) mice islet cells.

Liver findings in patients with Carney complex, germline PRKAR1A pathogenic variants, and link to cardiac myxomas.

This study aimed to evaluate liver involvement in patients with Carney complex (CNC) based on a large cohort and to analyze any germline PRKAR1A genotype-phenotype association of liver disease. The study included 83 patients with CNC, followed between 1995 and 2018 at a tertiary research center. We reviewed liver images, recorded types and number of lesions and analyzed per genotype: all patients were sequenced for the PRKAR1A gene. A total of 29/83 patients (24.0%) had liver radiological findings. Patients with liver lesion had a significantly higher rate of pathogenic variants detected in the PRKAR1A gene (72.4 vs 38.9%, P = 0.005, respectively). Patients with a pathogenic variant detected on germline PRKAR1A analysis had a higher risk for having a liver lesion compared with patients with wild-type (WT) PRKAR1A alleles (21/42 (50.0%) vs 8/41 (19.5%), respectively, P = 0.004). Among patients with liver lesions, those with a nonsense PRKAR1A pathogenic-variant had more liver lesions (7/7) than among those with other pathogenic-variant types (8/22, P = 0.001). In multivariable analysis, detection of liver lesion(s) was associated with an odds ratio of 5.2 for cardiac myxomas (95% CI 1.55-17.49, P = 0.008). In conclusion, patients with CNC, particularly with a PRKAR1A pathogenic variant, have a higher rate of liver lesions. Additionally, liver lesions are associated with a high risk for cardiac myxomas in this population.

Failure to Thrive in the Context of Carney Complex.

BACKGROUND/AIMS: Carney complex (CNC) is a rare syndrome associated with multiple tumors and several other unique manifestations. We describe the clinical, genetic, and laboratory findings in a cohort of patients with CNC and failure to thrive (FTT). METHODS: A retrospective case series of pediatric patients with CNC presenting with FTT. RESULTS: We describe a patient with infantile Cushing syndrome (CS) who presented with severe FTT and liver disease; the patient was subsequently diagnosed with CNC. This led to the realization that at least 10 other patients with CNC and FTT have been investigated in the last 22 years at the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Four of those had primary pigmented nodular adrenocortical disease (PPNAD), 2 had cardiac myxomas, and 3 had liver disease. CONCLUSION: Pediatric patients with CNC may present with FTT whose primary cause is variable and includes CS due to PPNAD, hepatic involvement, and other manifestations of CNC. FTT due to liver disease and/or other causes is a unique new presentation of this rare syndrome with which clinicians need to be familiar.

Is infection with hypermutable Pseudomonas aeruginosa clinically significant?

BACKGROUND: Hypermutable Pseudomonas aeruginosa (HPA) with high mutation rate due to defects in the DNA mismatch repair genes are frequently isolated in the sputum of cystic fibrosis (CF) patients. These isolates tend to be multidrug resistant and may be better adapted to the CF lung environment. However, the clinical significance of this infection has not been determined. METHODS: This prospective study enrolled patients with PA infection attending CF clinics in Jerusalem between 2010 and 2011. Mutation frequency of pseudomonas isolates was determined by quantification of colonies resistant to rifampicin. RESULTS: Of the 73 patients enrolled, 22 (30%) were infected with HPA. Average mutation frequency was 2.95×10(-4) in HPA and 1×10(-7) in non-HPA. Pulmonary function tests, number of pulmonary exacerbations and the response to antibiotic therapy were similar between patients infected with HPA and non-HPA isolates. The only predictors for infection with HPA were resistance to multiple antimicrobial categories (OR=4.8, 95% CI: 1.8-12.4) and previous use of inhaled colistin (OR=8.1, 95% CI: 2-30). Resistant mutant subpopulation analysis was a poor screening test for identifying HPA isolates. CONCLUSIONS: Infection with hypermutable strains represents the marked ability of PA to adapt to the lung environment, but was not associated with worse clinical outcome.